Elucidating the Structures of Amyloid Oligomers with Macrocyclic β-Hairpin Peptides: Insights into Alzheimer's Disease and Other Amyloid Diseases.
Elucidating the Structures of Amyloid Oligomers with Macrocyclic β-Hairpin Peptides: Insights into Alzheimer's Disease and Other Amyloid Diseases.
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DOI：
10.1021/acs.accounts.7b00554
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发表时间：
2018-03-20
影响因子：
18.3
通讯作者：
Nowick JS
中科院分区：
文献类型：
--
作者：
Kreutzer AG;Nowick JS
自其被发现以来的世纪里，阿尔茨海默病已成为淀粉样蛋白疾病的典型。阿尔茨海默氏病的化学基础的第一次一瞥始于1892年在大脑中鉴定出“淀粉样蛋白”斑块，并在1968年扩展到鉴定出具有“交叉β”结构的蛋白质纤维。进一步的努力导致发现β-淀粉样肽Aβ作为一种40或42个氨基酸的肽，负责斑块和纤维。在这一点上，长达三十年的马拉松开始阐明原纤维的结构，并确定阿尔茨海默病的分子基础。沿着，一种替代模型开始出现，在这种模型中，Aβ的小聚集体（称为“寡聚体”），而不是原纤维，是导致阿尔茨海默病神经退行性变的罪魁祸首。这个帐户描述了什么是已知的原纤维的结构，并详细介绍了我们的研究小组的努力，以了解淀粉样蛋白疾病中的低聚物的结构，生物物理和生物学特性。β-折叠是淀粉样蛋白原纤维和低聚物的结构单元。淀粉样原纤维通常由平行β-折叠的延伸网络组成。淀粉样蛋白寡聚体似乎是更紧凑的封闭结构，其中一些被认为是由包含β-发夹的反平行β-折叠组成。β-发夹是特殊的，因为它们的扭曲形状，疏水表面和暴露的氢键边缘赋予形成紧凑组装体的独特倾向。我们的实验室已经开发了大环β-折叠，其被设计用于模拟由淀粉样蛋白生成肽和蛋白质形成的β-发夹。β-发夹模拟物含有两个β-链肽片段，通过两个δ-连接的鸟氨酸转角模拟物在其N-和C-末端连接在一起以产生大环。在β链之一上安装N-甲基以防止不受控制的聚集。这些设计特征有助于β-发夹模拟物的结晶和它们形成的低聚物的X射线晶体学结构的测定。在过去的几年里，我们的实验室已经阐明了由Aβ、α-突触核蛋白和β2-微球蛋白衍生的β-发夹模拟物形成的寡聚体的X射线晶体学结构。在这三种淀粉样蛋白生成肽和蛋白质中，Aβ β-发夹模拟物提供了对淀粉样蛋白寡聚体的最深入了解。我们的研究揭示了一种以前未发现的自组装模式，即三个Aβ β-发夹模拟物组装形成三角形三聚体。三角形三聚体是引人注目的，因为它们含有两个大部分疏水的表面，与其他三角形三聚体包装在一起形成更高级的低聚物，如六聚体和十二聚体。一些十二聚体填充在晶格中以形成环形孔状组装体。一些β-发夹模拟物和三角形三聚体在溶液中组装形成寡聚体，其重现了晶体学上观察到的寡聚体。这些寡聚体对神经源性细胞表现出毒性，重现了由全长淀粉样蛋白生成肽和蛋白质形成的寡聚体的毒性。这些发现意义重大，因为它们解决了理解淀粉样蛋白疾病分子基础的空白。我们预计这些研究将为开发诊断和治疗方法铺平道路，以对抗阿尔茨海默病，帕金森病和其他淀粉样蛋白疾病。
In the more than a century since its identification, Alzheimer’s disease has become the archetype of amyloid diseases. The first glimpses of the chemical basis of Alzheimer’s disease began with the identification of “amyloid” plaques in the brain in 1892 and extended to the identification of proteinaceous fibrils with “cross-β” structure in 1968. Further efforts led to the discovery of the β-amyloid peptide Aβ as a 40- or 42-amino acid peptide that is responsible for the plaques and fibrils. At this point, a three-decade long marathon began to elucidate the structure of the fibrils and identify the molecular basis of Alzheimer’s disease. Along the way, an alternative model began to emerge in which small aggregates of Aβ, called “oligomers”, rather than fibrils, are the culprits that lead to neurodegeneration in Alzheimer’s disease. This Account describes what is known about the structures of the fibrils and details our research group’s efforts to understand the structural, biophysical, and biological properties of the oligomers in amyloid diseases. β-Sheets are the building blocks of amyloid fibrils and oligomers. Amyloid fibrils generally consist of extended networks of parallel β-sheets. Amyloid oligomers appear to be more compact enclosed structures, some of which are thought to be composed of antiparallel β-sheets comprising β-hairpins. β-Hairpins are special because their twisted shape, hydrophobic surfaces, and exposed hydrogen-bonding edges impart a unique propensity to form compact assemblies. Our laboratory has developed macrocyclic β-sheets that are designed to mimic β-hairpins formed by amyloidogenic peptides and proteins. The β-hairpin mimics contain two β-strand peptide fragments linked together at their N- and C-termini by two δ-linked ornithine turn mimics to create a macrocycle. An N-methyl group is installed on one of the β-strands to prevent uncontrolled aggregation. These design features facilitate crystallization of the β-hairpin mimics and determination of the X-ray crystallographic structures of the oligomers that they form. During the past few years, our laboratory has elucidated the X-ray crystallographic structures of oligomers formed by β-hairpin mimics derived from Aβ, α-synuclein, and β2-microglobulin. Out of these three amyloidogenic peptides and proteins, the Aβ β-hairpin mimics have provided the most insight into amyloid oligomers. Our studies have revealed a previously undiscovered mode of self-assembly, whereby three Aβ β-hairpin mimics assemble to form a triangular trimer. The triangular trimers are remarkable, because they contain two largely hydrophobic surfaces that pack together with other triangular trimers to form higher-order oligomers, such as hexamers and dodecamers. Some of the dodecamers pack in the crystal lattice to form annular porelike assemblies. Some of the β-hairpin mimics and triangular trimers assemble in solution to form oligomers that recapitulate the crystallographically observed oligomers. These oligomers exhibit toxicity toward neuronally derived cells, recapitulating the toxicity of the oligomers formed by full-length amyloidogenic peptides and proteins. These findings are significant, because they address a gap in understanding the molecular basis of amyloid diseases. We anticipate that these studies will pave the way for developing diagnostics and therapeutics to combat Alzheimer’s disease, Parkinson’s disease, and other amyloid diseases.
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影响因子：
21.8
作者：
通讯作者：
--
DOI：
10.1126/science.aao2825
发表时间：
2017-10-06
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Gremer L;Schölzel D;Schenk C;Reinartz E;Labahn J;Ravelli RBG;Tusche M;Lopez-Iglesias C;Hoyer W;Heise H;Willbold D;Schröder GF
通讯作者：
Schröder GF
影响因子：
2.9
作者：
Petkova, AT;Yau, WM;Tycko, R
通讯作者：
Tycko, R
DOI：
10.1073/pnas.0711731105
发表时间：
2008-04-01
影响因子：
11.1
作者：
Hoyer, Wolfgang;Gronwall, Caroline;Hard, Torleif
通讯作者：
Hard, Torleif
影响因子：
5.2
作者：
Salveson, Patrick J.;Spencer, Ryan K.;Nowick, James S.
通讯作者：
Nowick, James S.